The Debut of the Quad Pill

Pharmaceutical companies are increasingly putting two or more drugs into one pill; these are called fixed-dose co-formulations. One company that makes several co-formulations is Gilead Sciences, which sells the following anti-HIV drugs:

tenofovir (Viread)

FTC (emtricitabine, Emtriva)

Truvada (tenofovir + FTC)

Atripla (efavirenz + tenofovir + FTC)

Gilead is currently developing another anti-HIV drug, called elvitegravir, which belongs to the class of drugs called integrase inhibitors. These drugs work by impairing the activity of an enzyme called integrase, which is needed by HIV-infected cells to make new copies of HIV.

Elvitegravir needs to be taken with a booster -- another drug that helps to raise and maintain levels of elvitegravir in the blood for a prolonged period. The impact of boosting results in a once-daily dosing requirement of elvitegravir. The booster that Gilead Sciences has been developing is called GS-9350 or cobicistat; there is currently no publicly available brand name for this compound.

Gilead has combined the following four drugs into one pill called a "quad":

elvitegravir

cobicistat

tenofovir

FTC

At a dose of 150 mg per day, cobicistat can boost not only elvitegravir but also another anti-HIV drug called atazanavir (Reyataz). Atazanavir is sometimes taken with another booster called ritonavir (Norvir).

Gilead has conducted two short-term placebo-controlled Phase II studies to compare the preliminary safety and efficacy of the following combinations of drugs:

The quad pill shows excellent anti-HIV activity and appears to be well tolerated. However, larger and longer comparative studies called Phase III clinical trials are needed to assess the effects of the quad and other combinations that use cobicistat.

Study Details

Researchers assigned HIV-positive volunteers to the following combinations:

quad: 48 people

Atripla: 23 people

atazanavir + Truvada + cobicistat: 50 people

atazanavir + Truvada + ritonavir: 29 people

The average profile of participants at the start of the studies was as follows:

10% females, 90% males

age: 36 years

CD4+ count: 350 cells

viral load: 40,000 copies/mL

about 25% of participants had a viral load greater than 100,000 copies/mL

Results

After 24 weeks the proportion of participants with a viral load in their blood less than 50 copies/mL in each group was as follows:

quad: 90%

Atripla: 83%

atazanavir + Truvada + cobicistat: 84%

atazanavir + Truvada + ritonavir: 86%

As previously mentioned, the quad pill contains the integrase inhibitor elvitegravir; in the present study viral loads fell rapidly in participants who received elvitegravir. In previous studies with the first approved integrase inhibitor, raltegravir (Isentress), viral loads also fell rapidly.

Bear in mind that the number of study volunteers was modest and firm conclusions about the long-term effectiveness of the quad pill or the safety of cobicistat cannot yet be drawn. Nevertheless, the quad pill will likely be at least roughly equivalent in effectiveness to Atripla. Phase III trials comparing the quad to Atripla are expected to begin later in 2010.

Safety

As new drugs get tested, it is important to assess their potential for side effects. Here are the overall proportions of participants who experienced side effects of any intensity:

quad: 35%

Atripla: 57%

atazanavir + Truvada + cobicistat: 20%

atazanavir + Truvada + ritonavir: 24%

Here is the distribution of some of the selected side effects:

Abnormal Dreams, Nightmares

quad: 10%

Atripla: 35%

atazanavir + Truvada + cobicistat: 0%

atazanavir + Truvada + ritonavir: 0%

Fatigue

quad: 8%

Atripla: 13%

atazanavir + Truvada + cobicistat: 2%

atazanavir + Truvada + ritonavir: 7%

Nausea

quad: 4%

Atripla: 4%

atazanavir + Truvada + cobicistat: 10%

atazanavir + Truvada + ritonavir: 3%

Diarrhea

quad: 8%

Atripla: 4%

atazanavir + Truvada + cobicistat: 6%

atazanavir + Truvada + ritonavir: 10%

Here is the proportion of participants who had moderate-to-severe elevations in the amount of total cholesterol in their blood:

quad: 9%

Atripla: 10%

atazanavir + Truvada + cobicistat: 6%

atazanavir + Truvada + ritonavir: 0%

Similar changes were seen for good (HDL) and bad (LDL) cholesterol as well as triglycerides.

Here is the proportion of participants who had elevated levels of protein in their urine, suggestive of kidney damage:

quad: 2%

Atripla: 10%

atazanavir + Truvada + cobicistat: 4%

atazanavir + Truvada + ritonavir: 0%

Here is the proportion of participants who had mild decreases in levels of creatinine in their blood, also suggestive of kidney damage:

quad: 2%

Atripla: 0%

atazanavir + Truvada + cobicistat: 12%

atazanavir + Truvada + ritonavir: 0%

Here is the proportion of participants who had less-than-normal levels of phosphorus in the blood, also suggestive of kidney damage:

quad: 0%

Atripla: 0%

atazanavir + Truvada + cobicistat: 2%

atazanavir + Truvada + ritonavir: 3%

Here is the proportion of participants who had moderate-to-severe elevations in the levels of the liver enzyme ALT in their blood, suggestive of liver damage:

quad: 0%

Atripla: 0%

atazanavir + Truvada + cobicistat: 2%

atazanavir + Truvada + ritonavir: 3%

Here is the proportion of participants who had moderate-to-severe elevations in the levels of the liver enzyme AST in their blood, suggestive of liver damage:

quad: 0%

Atripla: 0%

atazanavir + Truvada + cobicistat: 0%

atazanavir + Truvada + ritonavir: 3%

Here is the proportion of participants who had moderate-to-severe elevations in the level of the waste product bilirubin in their blood:

quad: 0%

Atripla: 0%

atazanavir + Truvada + cobicistat: 82%

atazanavir + Truvada + ritonavir: 86%

Overall, the results from these Phase II trials suggest that combinations that use cobicistat have potent anti-HIV activity. However, larger and longer comparative trials -- Phase III studies -- are needed to determine the effectiveness of these new combinations over the long-term.

Although there were a modest number of volunteers in the studies, cobicistat appears to increase lipid levels to a similar degree as efavirenz (Sustiva and in Atripla) or ritonavir. This finding needs to be explored in larger Phase III studies. Similarly, cobicistat's impact on kidney health and a possible interaction between atazanavir and tenofovir and their impact on kidney health need to be further assessed. The potential for cobicistat to interact with other medications commonly used by HIV-positive people is also something that requires further study.

Reference

Cohen C, Shamblaw D, Ruane P, et al. Single-tablet, fixed-dose regimen of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 achieves a high rate of virologic suppression and GS-9350 is an effective booster. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February 2010, San Francisco, U.S. Abstract 58 LB.

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